Conventionally, non-narcotic analgesics have been administered to patients in dosage forms such as oral, injectable and suppository preparations. However, oral preparations may have the problem of poor absorption, low bioavailability or the like, whereas injectable preparations have the disadvantage of requiring frequent administration and therefore causing pain and inconvenience to patients. On the other hand, although suppository preparations improve the above disadvantages of oral and injectable preparations in some ways, they have the disadvantage of great inconvenience and discomfort of patients due to the administration route.
In recent years, a wide variety of studies on transdermal absorption of drugs have been carried out in order to solve the disadvantages of various dosage forms as described above and moreover to use the characteristics of transdermal administration preparations that can deliver drugs at a controlled rate for a long term compared with injectable preparations and oral administration preparations. However, when drugs are administered transdermally, there is the fundamental problem that it is difficult to improve skin permeability of drugs since the stratum corneum on the skin surface has a barrier function against drug permeation. Therefore, it is essential to enhance the transdermal absorbability of drugs in some way so as to allow drugs to be absorbed transdermally in an effective manner. In order to solve this problem, there have been studied and developed absorption enhancers and transdermal absorption devices.
For example, eptazocine, which is one of non-narcotic analgesics, is used for various types of cancer pain, postoperative pain and the like, and has excellent characteristics of fewer side effects such as physical dependence and respiratory depression compared with other non-narcotic analgesics. Currently, only injectable preparations of eptazocine hydrobromide are commercially available as eptazocine preparations. However, injectable preparations require frequent administration due to its short half-life in blood and therefore cause pain to patients upon administration, and also require patients to go to hospital regularly, resulting in inconvenience. For these reasons, there is a demand for the development of preparations for external use which allow a therapeutically sufficient amount of drugs to be absorbed transdermally in a sustained manner; however, hitherto there has been no technique to increase the transdermal absorbability in a sustained manner to a practical level, so that such preparations for external use have not been put into practical use.
As for transdermally absorbed preparations of non-narcotic analgesics, Patent Document 1 discloses that the combined use of pentazocine with isopropyl myristate and caprylic acid monoglyceride (glyceryl monocaprylate) which are transdermal absorption enhancers improves the skin permeability. In a scientific meeting, there has been reported a composition containing isopropyl myristate and a glycerin fatty acid ester which are the same as the transdermal absorption enhancers used in Patent Document 1 in addition to eptazocine (See Non-Patent Document 1). However, as described in both documents, pharmaceutical compositions containing pentazocine or eptazocine and, as absorption enhancers, a fatty acid ester such as isopropyl myristate and a glycerin fatty acid ester such as caprylic acid monoglyceride are all in the form (dosage form) of a liquid (solution or suspension). Drugs in liquid dosage form may be excellent in skin permeability in some cases; however, such drugs themselves are difficult to be applied as a preparation for external use which exerts drug efficacy sustainably for a long term.
Accordingly, the present inventors have tried to formulate the eptazocine-containing pharmaceutical composition in suspension form described in Non-Patent Document 1 into a patch preparation. In the case of suspensions, there is the problem that suspensions should be made into patch preparations by maintaining their uniformly dispersed state. Therefore, the present inventors have produced a matrix-type patch preparation which is a transdermal administration preparation that can uniformly disperse and hold drugs. As for acrylic adhesives which are most commonly used as a matrix, the present inventors have produced matrix-type patch preparations with various acrylic adhesives and tested their transdermal absorbability; however, good results have not been obtained. That is, even with eptazocine-containing matrices, each having a high concentration of 10% or 20% by weight, the skin permeation rate of eptazocine is 2 to 23 g/cm2/hr (See Reference Example 1), and there have not been obtained preparations which can deliver the drug into the body with satisfactory permeability.
Despite this, the present inventors have found out that, when eptazocine in free form is prepared into an organogel containing a fatty acid ester and a glycerin fatty acid ester, the resulting organogel shows significant skin permeability. On the other hand, when eptazocine hydrobromide which is the same as the active ingredient of commercially available injectable preparations is prepared into the organogel, the resulting organogel has lower skin permeability characteristics than that of the preparation in suspension form described in Non-Patent Document 1 (See Example 1). This reveals that simply applying the drug in liquid form to an organogel does not necessarily provide excellent skin permeability.
Meanwhile, it is found that this pharmaceutical composition for external use in organogel form according to the present invention has excellent skin permeability for not only eptazocine in free form but also other drugs such as tramadol and pentazocine in free form. Further, preparations in matrix or gel form are considered to be generally low in drug release rate of preparations due to the restriction of drug release compared with preparations in liquid form having flowability; however, surprisingly, the pharmaceutical composition for external use according to the present invention shows a very high drug release rate that exceeds that of the preparation in liquid form (See Example 1). This means that little drug remains in the applied composition, which is a highly beneficial feature in preparations in practical use.